Natural killer (NK) cells eliminate virus-infected cells and tumor cells through direct cytolysis they also influence the immune response through the production of pro-inflammatory cytokines. NK cells recognize their target cells via activating and inhibitor receptors that sense the presence of stress- or virus-induced ligands or the presence of self-MHC Class I, respectively. It is not known what regulates the expression and function of these receptors on NK cells. The transcription factor Ets1 is a known oncogene but is also required for proper NK development and function. Mice deficient in Ets1 have reduced numbers of NK cells with altered expression of NK receptors. The few mature NK cells that are present in Ets1-/- mice are in a state of chronic activation, indicating that Ets1 regulates genes important i these processes. Our long-term plan is to determine what genes Ets1 regulates during NK cell development and activation. Chromatin immuno-preciptitaion with high throughput DNA sequencing will be used to identify unique Ets1 targets in mature NK cells. We will determine whether activating receptors are direct targets of Ets1 and whether Ets1 cooperates with other NK cell-associated factors to regulate gene expression. NK cells that do not express Ets1 have a lower expression of activating receptors and high expression of transcription factors correlated with chronic activation. We plan to use retroviral transduction to manipulate the expression of these molecules in Ets1 deficient NK cells to determine if these molecules are responsible for the chronic activation state. We will also determine if the reduced number of NK cells in Ets1-deficient mice is the result of leaky granzyme molecules made by the NK cells. Ultimately, we hope that this knowledge can be used to manipulate NK cell development and function to promote the removal of cancerous cells.